Inhibitory Circuit Compensations in Female and Male Mice: Increased Synaptic Output Offsets Reduced Parvalbumin Interneuron Density

Summary Parvalbumin inhibitory interneurons (PV-INs) are critical regulators of excitatory/inhibitory balance in the cortex, and their dysfunction has been observed in various neurological disorders. Despite increasing recognition of sex differences in brain function, little is known about how PV-INs differ between males and females under healthy conditions. Previous work has pointed to sex differences in PV-IN vulnerability in disease and injury models. Here, we investigated sex differences in PV-IN characteristics, connectivity, and function in the retrosplenial cortex (RSC) of healthy mice. We found that female mice have significantly fewer PV-INs in the RSC compared to males, yet exhibit comparable memory induced neuronal activation (fos expression). Despite their lower numbers, female PV-INs displayed greater synaptic connectivity, as evidenced by increased synaptotagmin-2 (Syt-2) puncta per PV-IN and higher axonal bouton density. Additionally, fewer female PV-INs were surrounded by perineuronal nets (PNNs), suggesting greater plasticity in female inhibitory networks. From ex vivo slice electrophysiology recordings we observed greater excitability in female PV-INs compared to male PV-INs and, a reduced incidence of IPSCs. These findings indicate that female mice may compensate for reduced PV-IN numbers through enhanced synaptic output, preserving inhibitory function in the RSC. Finally, using spatial transcriptomic profiling of PV-INs we observed a number of differentially expressed genes that are consistent with the observed structural and functional differences between female and male PV-INs. Understanding these sex-specific inhibitory mechanisms is crucial for developing more targeted interventions for conditions involving PV-IN impairment and for understanding sex specific vulnerabilities to certain conditions such as Alzheimer’s disease.